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Cited by 43Endoplasmic Reticulum Stress and DiseaseCancer, Hypoxia, and MetabolismCell death mechanisms and regulation

The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment

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Bartoszewska, Sylwia, Collawn, James F., Bartoszewski, Rafal·2022·Cancers
DOI 10.3390/cancers14194870PMC PMC9562011
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Abstract

Despite our understanding of the unfolded protein response (UPR) pathways, the crosstalk between the UPR and the complex signaling networks that different cancers utilize for cell survival remains to be, in most cases, a difficult research barrier. A major problem is the constant variability of different cancer types and the different stages of cancer as well as the complexity of the tumor microenvironments (TME). This complexity often leads to apparently contradictory results. Furthermore, the majority of the studies that have been conducted have utilized two-dimensional in vitro cultures of cancer cells that were exposed to continuous hypoxia, and this approach may not mimic the dynamic and cyclic conditions that are found in solid tumors. Here, we discuss the role of intermittent hypoxia, one of inducers of the UPR in the cellular component of TME, and the way in which intermittent hypoxia induces high levels of reactive oxygen species, the activation of the UPR, and the way in which cancer cells modulate the UPR to aid in their survival. Although the past decade has resulted in defining the complex, novel non-coding RNA-based regulatory networks that modulate the means by which hypoxia influences the UPR, we are now just to beginning to understand some of the connections between hypoxia, the UPR, and the TME.

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  • HIF activation drives tumor progression by coordinating transcriptional programs that promote glycolytic metabolism, angiogenic factor production, cell survival, proliferation, immune evasion, and maintenance of cancer stem-like properties.

    “From a mechanistic standpoint, HIF activation drives tumor progression by coordinating transcriptional programs that promote glycolytic metabolism, angiogenic factor production, cell survival, proliferation, immune evasion, and maintenance of cancer stem like properties [20,250,251].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [20]

    The Introduction and Section 2 state that HIF-driven transcriptional changes shift metabolism toward glycolysis, promote angiogenesis and cell survival, and enhance tumor growth. The copy does not establish that HIF transcriptional programs promote immune evasion or maintain cancer stem-like properties; Section 4 instead discusses impaired immune recognition as an effect of the UPR. Proliferation is supported only at the broader level of enhanced tumor growth. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Suppression of hypoxia-driven angiogenesis and metabolic plasticity is desirable in pathological settings such as solid tumors and pathological neovascular eye conditions.

    “In contrast, suppression of hypoxia-driven angiogenesis and metabolic plasticity is desirable in pathological settings such as solid tumors [[18], [19], [20]] and pathological neovascular eye conditions”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [20]

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Cited by

Sorted by citations

Authors
Bartoszewska, S., Collawn, J. F., & Bartoszewski, R.
Affiliations
  • Gdańsk Medical University (PL)
  • University of Alabama at Birmingham (US)
  • Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a Street, 50-383 Wroclaw, Poland
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2022-10-05
Volume
14
Issue
19
Pages
4870
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers14194870
PMC
PMC9562011
OpenAlex
W4303621995
Cited by
43
References
26
Citations by year
2026: 14 · 2025: 6 · 2024: 12 · 2023: 9 · 2022: 2
FWCI
1.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Center “OPUS” 2020/37/B/NZ3/00861 Program
  • MUGs’ Experienced Researcher Program
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
unfolded protein response, tumor microenvironment, hypoxia, intermittent hypoxia, reactive oxygen species, tumor cell survival, non-coding RNA, endoplasmic reticulum stress, solid tumors

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